Eosinophilic gastrointestinal disorders (EGIDs) are a group of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past decade, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EoE), but also eosinophilic gastroenteritis (EG). EGID patients often have numerous food hypersensitivities, and the disease goes into remission with the institution of an amino acid based elemental diet. In sum, this suggests that EGID is a food allergen driven eosinophilic inflammatory gut disease. In our previous work we have demonstrated that IL-5+ Th2 cells are associated with EGID, but not anaphylactic forms of food allergy. We have further characterized these IL-5+ Th2 cells as more highly differentiated Th2 cells that are the product of multiple rounds of antigenic stimulus. In sum, these findings suggest that IL-5+ Th2 cells may be the major pathway driving eosinophilic gut inflammation in EGID. However, these previous investigations have been limited to blood T cells. Current work is underway to extend these findings to gut resident T cells in patients with eosinophilic GI disease. GI biopsies will be obtained and both flow cytometry and immunohistochemisty will be used to determine if a similar association with IL-5+ Th2 cells exists. In collaborative work we have applied the polychromatic flow cytometry techniques used to characterized Th2 subpopulations in EGID to other immunological diseases. As part of a collaboration with Dr. Amy Klion's group in the Laboratory of Parasitic Diseases, we have characterized the cytokine phenotype of the clonal Th2 subpopulation in an unusual case of lymphocytic hypereosinophilic syndrome. As part of a collaboration with Dr. Ash Jain's group in the Laboratory of Host Defenses, we have examined immunomodulation by an agonistic anti-CD40 monoclonal antibody in subjects with X-linked hyper-IgM syndrome (XHM) and biliary Cryptosporidiosis. Treatment with anti-CD40 resulted in an increased in Th1 cells and in 1 of 2 subjects, transient clearing of the Cryptosporidia.